Analysis of Related Risk Factors and Prognostic Factors of Gastric Cancer with Bone Metastasis: A SEER-Based Study

Background Gastric cancer is among the most common malignant tumors at home and abroad, because its early symptoms are mostly insidious, which leads to distant metastasis when gastric cancer is first diagnosed. The common metastatic sites of gastric cancer are mainly the liver, lung, and peritoneum, but bone metastasis is relatively rare, and the prognosis of gastric cancer bone metastasis is very poor. Therefore, this study is built on the SEER database to analyze the related risk factors of gastric cancer bone metastasis and related factors affecting the prognosis of gastric cancer patients, aiming at improving clinicians' understanding of clinical diagnosis and prognosis of bone metastasis of gastric cancer, thus reducing misdiagnosis and missed diagnosis. Methods The SEER database was collected to screen out patients with gastric cancer bone metastases and nonbone metastases matched with them from 2010 to 2016, and the Kaplan-Meier method was used to draw survival curves, and the comparison between survival curves was performed by Log-rank test to analyze the overall survival of the two groups of patient's time. Logistic regression analysis was used to analyze the related risk factors of gastric cancer bone metastasis, and the Cox regression proportional hazard model was used to analyze the relationship between gastric cancer bone metastasis and patient prognosis. Results Using Kaplan-Meier survival curve to analyze the 1, 3, and 5-year survival rates of gastric cancer patients with bone metastasis and non-metastasis groups were 14.2%, 1.8%, 0.6% and 71.4%, 44.3%, 36.4%, respectively; the average survival rate of the metastatic group was The time was 4.0 months (95%CI: 3.475~4.525), and the average survival time of the non-metastatic group was 30.0 months (95%CI: 26.778~33.222). The difference between the two groups was statistically significant (χ2 = 1076.866, P < 0.001). Multivariate logistic regression analysis showed that race (P = 0.007, OR = 1.296), grade (P < 0.001, OR = 0.575), marital status (P < 0.001, OR = 0.040), tumor size (P = 0.006, OR = 0.752), TNM stage (P < 0.001), T stage (P = 0.023, OR = 0.882), and M stage (P < 0.001, OR = 44.958) are independent risk factors for gastric cancer bone metastasis. The Cox univariate analysis suggests that gastric cancer bone metastasis is a risk factor for the prognosis of gastric cancer patients. The Cox multivariate analysis validates that gastric cancer bone metastasis (HR = 0.584, 95% CI: 0.497~0.688, P < 0.001) is independent of the overall survival rate of gastric cancer patients. Conclusions Race, grade, marital status, tumor size, TNM stage, T stage, and M stage are independent risk factors for gastric cancer bone metastasis; and gastric cancer bone metastasis is an independent risk factor that affects the prognosis of gastric cancer patients. Therefore, for such high-risk groups, large range screening of the above indicators can effectively improve the prognosis of gastric cancer patients to a certain extent.


Introduction
Gastric cancer is a common malignant tumor. According to the statistics of GLOBOCAN in 2020 [1], there are about 1.089 million new cases of gastric cancer worldwide and about 769,000 deaths. The incidence and mortality of malignant tumors which are, respectively, No. 5 and No. 4 seriously affect the quality of life and health of patients. Most patients with gastric cancer have insidious onset and no obvious symptoms in the early stage. In addition, people's lack of understanding of the disease results in the clinical diagnosis of gastric cancer, which is mostly advanced and metastasized. This brings great difficulties to the treatment of the disease, which leads to the risk of gastric cancer patients. The survival period is short. Therefore, understanding the status of gastric cancer metastasis will help reduce the damage to the body caused by metastasis and improve the prognosis of gastric cancer patients.
The common metastatic sites of gastric cancer are the liver, lung, and peritoneum, while bone metastasis is relatively rare. Although studies have reported that the autopsy of gastric cancer patients found that the bone metastasis rate reached 13.4%-15.9%, related studies reported that the probability of gastric cancer bone metastasis is relatively low, only 0.9%-2.1% [2][3][4]. Although the probability of gastric cancer bone metastasis is low, patients with gastric cancer bone metastasis are mostly accompanied by systemic multiple organ failure, which makes the patient's prognosis poor and greatly reduces the efficacy. On the other hand, the current clinical studies related to the analysis of risk factors and prognostic factors of gastric cancer bone metastasis are limited to small sample analysis or case reports, and further studies are needed to confirm or supplement the accuracy of the results. Therefore, this study is based on the SEER database to analyze and explore the risk factors of advanced gastric cancer bone metastasis and factors affecting the prognosis of gastric cancer patients, aiming to provide evidence for the diagnosis and treatment of advanced gastric cancer bone metastasis and improve the prognosis of patients.

Materials and Methods
2.1. Study Population. The SEER database [5] is the full name of the National Cancer Institute Surveillance, Epidemiology, and End Results Program (Surveillance, Epidemiology, and End Results Program), which records in detail the various types of patients in different states and counties in the United States since 1973 Information, including age, gender, race, year of diagnosis, marital status, insurance, tumor size, lymphatic metastasis (TNM) staging, and distant organ metastasis. The SEER database released information on bone metastases from gastric cancer in 2010. Therefore, this study used SEER*Stat 8.3.6 software to extract the pathologically diagnosed cases of gastric cancer from 2010 to 2016. Inclusion criteria are as follows: (1) The primary tumor was located in the stomach when the patient was first diagnosed; (2) gastric cancer patients had only bone metastases; and (3) complete clinical, pathological, and follow-up data. Exclusion criteria are as follows: (1) Exclude secondary gastric cancer with bone metastasis; (2) gastric cancer without bone metastasis; (3) gastric cancer with liver or other sites metastasis; and (4) a large number of cases with incomplete data indicators.

Ethics and Consent.
For the institutional cohorts, data were extracted from the Surveillance, Epidemiology, and End Results database. This article does not contain any studies with human participants performed by any of the authors. For this type of study, formal consent is not required.

The Indicators
Included in the Analysis. The indicators included in the analysis are the following: age, gender, race,

Statistical
Analysis. SPSS 26.0 and GraphPad Prism 8.0 were used to analyze the data, and the count data was expressed in the form of percentage n (%), and the comparison between groups was performed by the χ 2 test. The Kaplan-Meier method was used to draw survival curves, and the comparison between survival curves was performed by Log-rank test to analyze the overall survival time of the two groups of patients. The logistic regression analysis was used to analyze the related risk factors of gastric cancer bone metastasis, and the Cox regression proportional hazard model was used to analyze the relationship between gastric cancer bone metastasis and patient prognosis. The difference was statistically significant with P < 0:05.

Comparison of Pathological Characteristics between
Patients with Gastric Cancer Bone Metastasis and Gastric Nonbone Metastasis. Bone metastasis of gastric cancer is related to age, race, tumor site, histological type, grade, insurance, marriage, tumor size, T stage, N stage, M stage, and TNM stage (P < 0:05) but has nothing to do with gender, radiotherapy, and chemotherapy (P > 0:05) (see Table 1).

Subsistence
Analysis. The average survival time of patients was 28.603 months (95% CI: 27.229~29.977), and the median follow-up time was 46 months (95% CI: 43.239~48.761). Among them, the median survival time of the bone metastasis group was 4.0 months (95% CI: 3.475~4.525) and the median survival time of the nonbone metastasis group was 30.0 months (95% CI: 26.778~33.222); patients with gastric cancer bone metastasis and nongastric cancer patients. The overall 1-year survival rates of patients with bone metastases were 14.2% and 71.4%, the 3-year survival rates were 1.8% and 44.3%, and the 5-year overall survival rates were 0.6% and 36.4%. The survival rate of the bone metastasis group was significantly lower than that of the nonmetastatic group. The overall survival rate difference between the two groups was statistically significant (χ 2 = 1076:866, P < 0:05, Figure 1).    , and it has nothing to do with gender, histological type, radiotherapy, and chemotherapy (P > 0:05) (see Table 2).  Table 3.  Table 4 and Figure 3.

Discussion
In recent years, with the continuous improvement of the medical level, the detection rate of patients with potential bone metastases in the screening of gastric cancer patients has increased significantly. According to related research reports, the proportion of patients with suspicious gastric cancer bone metastases found in gastric cancer screening through bone scans is as high as 25%-45.3% [6,7]. Therefore, further clinical research is needed to analyze the risk factors of gastric cancer patients with bone metastasis to improve the clinical diagnosis rate. In this study, through univariate analysis of relevant clinicopathological factors affecting bone metastasis in patients with gastric cancer, it was found that age, race,   Journal of Immunology Research tumor site, histological type, grade, insurance, marriage, tumor size, T stage, N stage, M stage, and TNM stage were related (P < 0:05) and have nothing to do with gender, radiotherapy, and chemotherapy (P > 0:05); in addition, through univariate and multivariate logistic stepwise regression analysis, the results suggest that race, grade, marriage, tumor size, T stage, M stage, and TNM stage are independent risk factors affecting bone metastasis of gastric cancer. Jingjing [8] analyzed the clinical data of 676 patients with gastric cancer in the First Affiliated Hospital of Zhengzhou University and found that the tumor TNM stage is an independent risk factor affecting gastric cancer bone metastasis, which is consistent with the results of this study. Min [9] also analyzed the risk factors related to gastric cancer bone metastasis and found that the degree of tumor differentiation was significantly related to gastric cancer bone metastasis, which was consistent with the results of this study. Bone metastasis mostly occurs in advanced gastric cancer, and the TNM stage of advanced gastric cancer is mostly at a higher value, and the degree of differentiation is lower than that in the early stage. These are the main reasons for gastric cancer bone metastasis. In our study, survival analysis found that gastric cancer bone metastasis was significantly correlated with the overall prognosis of patients. The survival time of gastric cancer patients with bone metastasis was significantly shortened, and the 5-year survival rate was significantly lower than that of the gastric cancer nonbone metastasis group (0.6% vs 36.4%, P < 0:05); on the other hand, the results of this study showed that the median survival time of patients with gastric cancer with bone metastases was 4 months, which was consistent with the results of Lee's study [10]. The overall low survival rate of patients with gastric cancer bone metastasis is mainly due to the fact that it mostly occurs in advanced gastric cancer. On the one hand, advanced gastric cancer surgery is difficult and high risk; on the other hand, gastric cancer bone metastasis can cause disseminated intravascular coagulation (DIC), leading to patients' coagulation dysfunction to appear, followed by thrombosis, leading to complications such as bleeding and severe anemia. These are all contraindications to chemotherapy, and chemotherapy is the main treatment for advanced gastric cancer; therefore, the prognosis of patients with gastric cancer and bone metastasis is often compared to other types of gastric cancer. Patients with malignant tumors are poor [11]. For advanced gastric cancer, the diagnosis and treatment effect are not obvious. It is necessary to clarify the principle of its occurrence and use effective means to intervene to reduce the occurrence of bone metastasis in advanced gastric cancer. However, the molecular mechanisms involved in the occurrence of bone metastasis in gastric cancer are still unclear, mainly including the following points: ①At present, lymphatic and blood tract metastases are mostly considered, and blood tract metastasis is mainly considered. It is considered that cancer cells flow into the liver through the blood and then enter the right heart to participate in systemic 7 Journal of Immunology Research circulation metastasis, while lymphatic metastasis mostly considered that cancer cells enter the systemic circulation through the thoracic duct to induce distant metastasis [12]; Chen et al. found that LNMAT1 can activate CCL2 by recruiting hnRNPL to the promoter region of CCL2 and stimulate VEGF through macrophages-C secretion to promote lymphatic metastasis, considering that gastric cancer may undergo lymphatic metastasis through this pathway [13]. ②The transcription factor Snail in gastric cancer cells inhibits the expression of miR-128 and activates the PI3K/ AKP pathway to induce high expression of Bim-1, thereby promoting the tumor EMT process and assisting tumor cell metastasis [14]. ③The CpG islands in the promoter fragment of lncRNA SPRY4-IT1 induce the expression of SPRY4-IT1 by inhibiting the activity of DNA methyltransferase 1 (DNMT1), thereby promoting tumor metastasis. It is considered that gastric cancer may undergo bone metastasis through this pathway [15]. ④Mast cell protease antibody (MCPT) can stimulate the formation of tumor blood vessels, thereby providing nutritional support for bone metastasis of gastric cancer [16].
In this study, it was found that bone metastasis of gastric cancer is an independent risk factor that affects the prognosis of gastric cancer patients by studying related risk factors that affect the prognosis of gastric cancer patients. This result is consistent with the results of Lee et al. [10]. Naka-nishi and others [17] pointed out that most patients with gastric cancer bone metastasis are accompanied by multiple sites, and most of the metastases are sites that are difficult to surgically remove. This is also the main reason for the poor prognosis of gastric cancer patients with bone metastases. In addition, the degree of differentiation, TNM stage, and tumor size are also independent risk factors that affect the prognosis of gastric cancer patients. The lower the degree of differentiation, the later the TNM stage, and the larger the tumor size, the poorer the prognosis of gastric cancer patients. Successively, Saito and Zhao also confirmed that the degree of tumor differentiation and tumor TNM staging is related to the prognosis of gastric cancer patients and can be used as an independent predictor of the prognosis of gastric cancer patients [18,19]. The correlation between tumor size and the prognosis of gastric cancer is still controversial. Kooby et al. [20] found that tumor size is related to the prognosis of gastric cancer patients and is an independent risk factor affecting the prognosis of gastric cancer patients. Huang et al. [21,22] believe that tumors are affected by many factors. The influence of factors, such as the operating skills of the surgeon, the depth of tumor invasion, and lymph node metastasis, cannot be used as factors to predict the prognosis of patients with gastric cancer.
This study has the following shortcomings: on the one hand, although the data sample size of this study is large, it  Journal of Immunology Research still has selection bias as a retrospective study; on the other hand, some of the more important prognostic indicators are CEA, alkaline phosphatase, imaging diagnosis, etc. The data is not recorded in the SEER database in detail, and it is impossible to analyze whether the above factors have an impact on gastric cancer bone metastasis and whether there is an impact on the prognosis of gastric cancer patients. It is still necessary to increase the sample size and reference indicators to further verify its accuracy. In addition, this research shows that the tumor size is second only to the TMN staging and has a high correlation. In summary, this article found through analysis, race, degree of differentiation, marriage, tumor size, TNM stage, T stage, and M stage are the independent risk factors affecting gastric cancer bone metastasis and gastric cancer metastasis is an independent risk factor affecting the prognosis of gastric cancer patients. Early detection of these risk factors is achieved by screening patients with gastric cancer. Diagnose and intervene as soon as possible in patients with gastric cancer bone metastases to effectively reduce the corresponding complications in patients with gastric cancer bone metastases and improve the prognosis of such patients.

Data Availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.